GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure

Nature Medicine, Journal Year: 2013, Volume and Issue: 19(5), P. 567 - 575

Published: March 31, 2013

Language: Английский

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Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Nature Reviews Endocrinology, Journal Year: 2016, Volume and Issue: 12(10), P. 566 - 592

Published: June 24, 2016

Language: Английский

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Insulin Signaling and Heart Failure

Circulation Research, Journal Year: 2016, Volume and Issue: 118(7), P. 1151 - 1169

Published: March 31, 2016

Heart failure is associated with generalized insulin resistance. Moreover, insulin-resistant states such as type 2 diabetes mellitus and obesity increases the risk of heart even after adjusting for traditional factors. Insulin resistance or alters systemic neurohumoral milieu, leading to changes in metabolism signaling pathways that may contribute myocardial dysfunction. In addition, within cardiomyocytes develop failing heart. The range from activation proximal adverse left ventricular remodeling mitochondrial dysfunction repression distal elements forkhead box O transcriptional glucose transport, which also impair cardiac metabolism, structure, function. This article will review complexities myocardium ways these are altered conditions implications therapeutic approaches treating preventing be discussed.

Language: Английский

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GLP-1 Receptor Activation Indirectly Reduces Hepatic Lipid Accumulation But Does Not Attenuate Development of Atherosclerosis in Diabetic Male ApoE−/− Mice

Endocrinology, Journal Year: 2012, Volume and Issue: 154(1), P. 127 - 139

Published: Nov. 27, 2012

Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce lipid accumulation in peripheral tissues, attenuating atherosclerosis and hepatic steatosis preclinical studies. We examined whether GLP-1R activation decreases progression high-fat diet-fed male ApoE(-/-) mice after administration of streptozotocin treatment with the long-acting agonist taspoglutide administered once monthly vs. metformin drinking water for 12 wk. Taspoglutide did not plaque area or content aortic arch abdominal aorta, no significant change macrophage was detected metformin. In contrast, triglyceride levels were significantly reduced livers from taspoglutide-treated mice. Both intracerebroventricular exendin-4 rapidly decreased plasma fasted mice, therapy modulated expression genes controlling fatty acid uptake oxidation. unable to detect entire Glp1r coding sequence macrophages isolated ApoE(-/-), C57BL/6, IL10(-/-) Similarly, mRNA transcripts RNA murine hepatocytes. Using Western blotting tissue extracts Glp1r(+/+) Glp1r(-/-) cells transfected a tagged cDNA, we could validate sensitivity specificity three different antisera commonly used detection protein. Taken together, these findings illustrate divergent actions on ectopic highlight importance indirect control accumulation.

Language: Английский

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Cardiovascular Actions of Incretin-Based Therapies

Circulation Research, Journal Year: 2014, Volume and Issue: 114(11), P. 1788 - 1803

Published: May 22, 2014

Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors represent 2 distinct classes of incretin-based therapies used for the treatment type diabetes mellitus. Activation GLP-1R signaling or inhibition DPP-4 activity produces a broad range overlapping unique cardiovascular actions. Native GLP-1 regulates biology via activation classical GLP-1R, through GLP-1(9-36), cardioactive metabolite generated by DPP-4-mediated cleavage. In contrast, clinically approved are not cleaved to GLP-1(9-36) produce majority their actions GLP-1R. The mechanisms engaged more complex, encompassing increased levels intact GLP-1, reduced changes in numerous peptides. Herein we review recent experimental clinical advances that reveal how affect normal diabetic heart coronary vasculature, often independent blood glucose. Improved understanding complex science is required optimize selection these therapeutic agents patients with disease.

Language: Английский

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Incretin Action in the Pancreas: Potential Promise, Possible Perils, and Pathological Pitfalls

Diabetes, Journal Year: 2013, Volume and Issue: 62(10), P. 3316 - 3323

Published: July 2, 2013

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that control the secretion of insulin, glucagon, somatostatin to facilitate glucose disposal. The actions terminated via enzymatic cleavage by dipeptidyl peptidase-4 (DPP-4) through renal clearance. GLP-1 GIP promote β-cell proliferation survival in rodents. DPP-4 inhibitors expand mass, reduce α-cell inhibit glucagon preclinical studies; however, whether incretin-based therapies sustain functional mass human diabetic subjects remains unclear. exert their predominantly unique G protein-coupled receptors expressed on β-cells other pancreatic cell types. Accurate localization receptor expression ductal or acinar cells normal pancreas is challenging because antisera used for detection often neither sufficiently sensitive nor specific yield reliable data. This article reviews recent advances controversies hormone action contrasts established mechanisms with areas uncertainty. Furthermore, methodological challenges pitfalls highlighted key requiring additional scientific investigation outlined.

Language: Английский

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Type 2 Diabetes Mellitus and Hypertension

Endocrinology and Metabolism Clinics of North America, Journal Year: 2013, Volume and Issue: 43(1), P. 103 - 122

Published: Dec. 12, 2013

Language: Английский

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Cardiovascular Effects of New Oral Glucose-Lowering Agents

Circulation Research, Journal Year: 2018, Volume and Issue: 122(10), P. 1439 - 1459

Published: May 10, 2018

Cardiovascular disease (CVD) is a major challenge in the management of type 2 diabetes mellitus. Glucose-lowering agents that reduce risk cardiovascular events would be considered advance, as recently reported with liraglutide and semaglutide, glucagon-like peptide-1 receptor agonists, empagliflozin canagliflozin, SGLT-2 (sodium-glucose cotransporter 2) inhibitors, but not DPP-4 (dipeptidyl peptidase-4) inhibitors. The present review devoted to CV effects new oral glucose-lowering agents. inhibitors (gliptins) showed some positive cardiac vascular preliminary studies, initial data from phase 3 clinical trials suggested reduction events. However, subsequent outcome alogliptin, saxagliptin, sitagliptin noninferiority failed demonstrate any superiority compared placebo patients mellitus high risk. An unexpected higher hospitalization for heart failure was saxagliptin. (gliflozins) promote glucosuria, thus reducing glucose toxicity body weight, enhance natriuresis, lowering blood pressure. Two mainly secondary prevention remarkable results. Empagliflozin EMPA-REG-OUTCOME (EMPAgliflozin OUTCOME Events Type Diabetes Mellitus Patients) reduced events, mortality, all-cause failure. In CANVAS (Canagliflozin Assessment Study), mortality canagliflozin reach statistical significance despite similar underlying protective mechanisms remain unknown both hemodynamic metabolic explanations have been proposed. CVD-REAL studies (Comparative Effectiveness Outcomes New Users Sodium-Glucose Cotransporter-2 Inhibitors; limitation an observational approach) these favorable results may class effect shared by all (including dapagliflozin) extrapolated larger population primary prevention. Ongoing other (linagliptin) (dapagliflozin, ertugliflozin) should provide additional information about pharmacological classes.

Language: Английский

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Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes

European Heart Journal, Journal Year: 2015, Volume and Issue: 36(34), P. 2288 - 2296

Published: June 10, 2015

Type 2 diabetes mellitus (T2DM) is characterized by multiple pathophysiologic abnormalities. With time, glucose-lowering medications are commonly required to reduce and maintain plasma glucose concentrations within the normal range. individuals also at a very high risk for microvascular complications incidence of heart attack stroke increased two- three-fold compared with non-diabetic individuals. Therefore, when selecting normalize levels in T2DM patients, it important that agent not aggravate, ideally even improve, cardiovascular factors (CVRFs) morbidity mortality. In this review, we examine effect oral (metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP4 inhibitors, SGLT2 α-glucosidase inhibitors) injectable (glucagon-like peptide-1 receptor agonists insulin) drugs on established CVRFs long-term studies outcomes. Firm evidence disease can be reversed or prevented improving glycaemic control still incomplete must await large, clinical trials patients low using modern treatment strategies, i.e. drug combinations designed maximize HbA1c reduction while minimizing hypoglycaemia excessive weight gain.

Language: Английский

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Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases

Journal of Endocrinology, Journal Year: 2013, Volume and Issue: 221(1), P. T31 - T41

Published: Sept. 2, 2013

The incretin hormone glucagon-like peptide 1 (GLP-1) has many effects in the body. It is best known for 'incretin effect', facilitating insulin release from pancreas under hyperglycaemic conditions. Building on this, GLP-1 mimetics have been developed as a treatment type 2 diabetes. In course of monitoring patients, it become apparent that range other physiological preclinical trials, substantial body evidence built these neuroprotective and anti-inflammatory effects. also very similar growth-factor-like properties to insulin, which presumably underlying basis studies Alzheimer's disease (AD), Parkinson's (PD), stroke neurodegenerative disorders, shown most cross blood-brain barrier show impressive numerous studies. animal models AD, such exendin-4, liraglutide lixisenatide protective CNS by reducing β-amyloid plaques, preventing loss synapses memory impairments, oxidative stress chronic inflammatory response brain. PD, exendin-4 showed protection dopaminergic neurons substantia nigra prevention dopamine basal ganglia while preserving motor control. These encouraging findings spawned several clinical some initial results. Therefore, great promise novel

Language: Английский

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